Candidate: Dr. Ghadially is a productive young scientist who has identified a new, clinically relevant area of investigation. She has the full support of her sponsor, Dr. Elias, an outstanding consultant in Dr. Feingold, and strong backing from her department chairman. Having described important structural, functional, and lipid biochemical abnormalities in chronically aged (CA) epidermis, Dr. Ghadially now plans to explore the potential role of aberrant cytokine signalling as a key cause of these abnormalities. This project is a logical next step to her prior work in epidermal aging and complements her sponsor's project on skin aging. As during her Dermatology Foundation Clinical Investigatorship, Dr. Ghadially will work closely with her sponsor, who will direct her growth toward independence in academic dermatology. Dr. Ghadially also will participate in the meetings of the scientific team working on the barrier and/or cytokines in Dermatology and Metabolism. By the end of this investigatorship, Dr. Ghadially will be able to sustain an independent laboratory research program on skin aging. Project: CA epidermis, even in the absence of photoaging, displays abnormalities in permeability barrier homeostasis, which become apparent only with stress. The applicant will examine cytokine expression in CA skin, and the possibility that aberrant cytokine signalling underlies these abnormalities. The epidermis generates an abundant, complex cytokine response to a variety of exogenous insults. Moreover, cytokine production changes with age in several extracutaneous tissues. Furthermore, cytokines such as TNF and IL-1a have been shown to regulate DNA synthesis in keratinocytes, as well as lipid metabolism in tissues such as liver and adipose tissue, which synthesize less lipid with age. The applicant first will assess whether CA epidermis displays abnormalities in the expression of one or more of the key regulatory cytokines, IL-1a, TNF, IL-1ra, and/or their receptors under basal conditions. Second, she will assess whether the epidermis mounts an aberrant cytokine response to various external insults. Third, the applicant will ascertain whether aberrant epidermal cytokine expression alone explains the alterations in barrier function, or whether dermal and/or systemic factors play a role. Finally, the applicant will attempt to correct the abnormalities in CA epidermis through administration of exogenous cytokines and to reproduce the aging phenotype by manipulating cytokine expression in young epidermis. The aged complain of a variety of problems, including dryness, pruritus, and scaling, that relate to alterations in barrier function. Yet, the consequences of epidermal aging are potentially of greater importance, including altered absorption of topical therapeutic products and abnormal susceptibility to exogenous pro-inflammatory/infectious insults. These studies could provide new therapeutic strategies to improve epidermal function in the aged.